The resistance to curative therapy in multiple myeloma (MM) may be linked to its genomic instability, accentuated by survival signals provided by the marrow microenvironment (ME). Toward the P01's grand theme of MM growth control, the overall goal of this project is to increase the frequency of durable CR as a prerequisite for long-term survival and to interpret treatment failure in the context of gene expression profiles (GEP) of both MM and ME. In the previous P01 funding cycle, 600 of eventually 660 patients were randomized to Total Therapy 2 (TT2) + thalidomide (THAL) and received post-transplant consolidation therapy. CR frequency was higher with added THAL (51% vs 36%, P=.002). For the 2/3 of patients lacking cytogenetic abnormalities (CA), 74% of TT2 (vs 40% of patients receiving predecessor TT1, P<.001) remained in continuous CR at 3 yr from onset of CR. The overall hypothesis for the new Project is that the ME provides MM-dependent sanctuary mechanisms that can be inactivated by agents co-targeting the ME and MM cells (THAL, dexamethasone, Revimid(R), and VelcadeTM). Thus, this project will pursue 3 major specific aims. Aim 1 will assess the long-term outcomes (event-free [EFS] and overall survival [OS]) and obstacles to sustaining CR among TT2 patients; TT2 patients who relapse or progress will be randomized to treatment with MM and ME co-targeting salvage therapies. In Aim 2, the successor to TT2--a phase 2 trial of TT3--will attempt to improve CR by incorporating Velcade (exhibiting marked activity in end-stage disease) into induction and consolidation therapies as part of melphalan-based tandem autotransplants and intersperse THAL and dexamethasone peri-transplant to provide continuous treatment during treatment-free gaps of TT2. Functional imaging will be used as a potential early prognostic indicator of improved treatment outcome. GEP analysis, in collaboration with Dr. Shaughnessy's project 3, will be used to discern MM-associated ME signatures and their alteration by therapies, to better understand mechanisms of treatment success or failure. In Aim 3, the maturing data of TT2 and TT3 trials will form the basis of TT4, which will be developed in Year 4 with the goal of introducing GEP-based risk-adapted therapy. Future studies generated by this P01 will test, in collaboration with NCI, promising novel agents for previously treated patients, once pre-clinical studies have validated that critical signaling pathways identified have indeed been targeted. Thus, in concert with 4 projects and access to 4 cores, this project will advance comprehensive treatment for sustained disease control in MM in a highly translational fashion.